Open Capsular Repair with Dermal allograft and tarsal tunnel release in the treatment of Tarsal Tunnel Syndrome in a Young Collegiate Athlete: A Case Report.

Tarsal tunnel syndrome is an entrapment neuropathy of the posterior tibial nerve beneath the flexor retinaculum that can be precipitated by either intrinsic or extrinsic factors. We report a unique case of a posterior medial ankle joint capsular defect with localized fluid extravasation between the flexor digitorum longus and flexor hallucis longus leading to symptoms consistent with tarsal tunnel syndrome in a collegiate tennis player. This patient is a 19-year-old female with no past medical history who presented with symptoms consistent with tarsal tunnel syndrome.

Subthreshold activation of the melanocortin system causes generalized sensitization to anorectic agents in mice.

The melanocortin-3 receptor (MC3R) regulates GABA release from agouti-related protein (AgRP) nerve terminals and thus tonically suppresses multiple circuits involved in feeding behavior and energy homeostasis. Here, we examined the role of the MC3R and the melanocortin system in regulating the response to various anorexigenic agents. The genetic deletion or pharmacological inhibition of the MC3R, or subthreshold doses of an MC4R agonist, improved the dose responsiveness to glucagon-like peptide 1 (GLP1) agonists, as assayed by inhibition of food intake and weight loss.

Structure of the Ion Channel Kir7.1 and Implications for its Function in Normal and Pathophysiologic States.

Hereditary defects in the function of the Kir7.1 in the retinal pigment epithelium are associated with the ocular diseases retinitis pigmentosa, Leber congenital amaurosis, and snowflake vitreal degeneration. Studies also suggest that Kir7.

Functional coupling between MC4R and Kir7.1 contributes to clozapine-induced hyperphagia.

Most antipsychotic drugs (APDs) induce hyperphagia and weight gain. However, the neural mechanisms are poorly understood, partly due to challenges replicating their metabolic effects in rodents. Here, we report a new mouse model that recapitulates overeating induced by clozapine, a widely prescribed APD.

Automated Patch Clamp Recordings of GPCR-Gated Ion Channels: Targeting the MC4-R/Kir7.1 Potassium Channel Complex.

Automated patch clamp recording is a valuable technique in drug discovery and the study of ion channels. It allows for the precise measurement and manipulation of channel currents, providing insights into their function and modulation by drugs or other compounds. The melanocortin 4 receptor (MC4-R) is a G protein-coupled receptor (GPCR) crucial to appetite regulation, energy balance, and body weight.

Novel Cocrystal Structures of Peptide Antagonists Bound to the Human Melanocortin Receptor 4 Unveil Unexplored Grounds for Structure-Based Drug Design.

Melanocortin 4 receptor (MC4-R) antagonists are actively sought for treating cancer cachexia. We determined the structures of complexes with and . These peptides differ from by substituting His with Pro and inserting Gly or Arg.

Inhibition of the melanocortin-3 receptor (MC3R) causes generalized sensitization to anorectic agents.

The melanocortin-3 receptor (MC3R) acts presynaptically to regulate GABA release from agouti-related protein (AgRP) nerve terminals and thus may be a negative regulator of multiple circuits involved in feeding behavior and energy homeostasis. Here, we examined the role of MC3R in regulating the response to various anorexigenic agents. Our findings reveal that genetic deletion or pharmacological inhibition of MC3R improves the dose responsiveness to Glucagon-like peptide 1 (GLP1) agonists, as assayed by inhibition of food intake and weight loss.

Melanocortin-3 receptor expression in AgRP neurons is required for normal activation of the neurons in response to energy deficiency.

The melanocortin-3 receptor (MC3R) is a negative regulator of the central melanocortin circuitry via presynaptic expression on agouti-related protein (AgRP) nerve terminals, from where it regulates GABA release onto secondary MC4R-expressing neurons. However, MC3R knockout (KO) mice also exhibit defective behavioral and neuroendocrine responses to fasting. Here, we demonstrate that MC3R KO mice exhibit defective activation of AgRP neurons in response to fasting, cold exposure, or ghrelin while exhibiting normal inhibition of AgRP neurons by sensory detection of food in the ad libitum-fed state.

Nail Plate Constructs are Associated with Decreased Rates of Reoperation in Complex Distal Femur Fractures.

Objectives: To determine if nail plate constructs have lower rates of reoperation to promote bone healing than lateral locking plates in the treatment of distal femur fractures.

Design: Retrospective Cohort.

Setting: Single Level 1 trauma centerPatients/Participants: 312 consecutive patients treated operatively for native distal femur fractures (OTA/AO 33A or 33C).

Aqueous remote loading of setmelanotide in poly(lactic-co-glycolic acid) microspheres for long-term obesity treatment.

Setmelanotide (Imcivree™) was developed as a daily injectable therapeutic peptide for the treatment of rare forms of syndromic obesity, such as POMC deficiency and leptin receptor deficiency. The important option of poly(lactic-co-glycolic acid) (PLGA) controlled release microspheres has become more attractive for this class of drugs upon the discovery that net positively charged peptides can be remote-loaded rapidly from aqueous peptide solution into blank microspheres at high loading and encapsulation efficiency. Here we sought to remote-load setmelanotide in PLGA microspheres and examine its potential for long-term controlled release and body weight control.

CRISPR/Cas9-mediated knock-in of masu salmon (Oncorhyncus masou) elongase gene in the melanocortin-4 (mc4r) coding region of channel catfish (Ictalurus punctatus) genome.

Channel catfish, Ictalurus punctatus, have limited ability to synthesize Ω-3 fatty acids. The ccβA-msElovl2 transgene containing masu salmon, Oncorhynchus masou, elongase gene driven by the common carp, Cyprinus carpio, β-actin promoter was inserted into the channel catfish melanocortin-4 receptor (mc4r) gene site using the two-hit two-oligo with plasmid (2H2OP) method. The best performing sgRNA resulted in a knockout mutation rate of 92%, a knock-in rate of 54% and a simultaneous knockout/knock-in rate of 49%.

Cell autonomous regulation of the activation of AgRP neurons by the melanocortin-3 receptor.

The melanocortin-3 receptor (MC3R) is a negative regulator of the central melanocortin circuitry via presynaptic expression on AgRP nerve terminals, from where it regulates GABA release onto secondary MC4R-expressing neurons. Hence, animals lacking MC3R (MC3R KO) exhibit hypersensitivity to MC4R agonists. However, MC3R KO mice also exhibit defective behavioral and neuroendocrine responses to fasting.

Targeting the central melanocortin system for the treatment of metabolic disorders.

A large body of preclinical and clinical data shows that the central melanocortin system is a promising therapeutic target for treating various metabolic disorders such as obesity and cachexia, as well as anorexia nervosa. Setmelanotide, which functions by engaging the central melanocortin circuitry, was approved by the FDA in 2020 for use in certain forms of syndromic obesity. Furthermore, the FDA approvals in 2019 of two peptide drugs targeting melanocortin receptors for the treatment of generalized hypoactive sexual desire disorder (bremelanotide) and erythropoietic protoporphyria-associated phototoxicity (afamelanotide) demonstrate the safety of this class of peptides.

Loss of Agrp1 in zebrafish: Effects on the growth and reproductive axis.

Loss of agouti related neuropeptide (AgRP) does not lead to overt phenotypes in mammals unless AgRP neurons are ablated. In contrast, in zebrafish it has been shown that Agrp1 loss of function (LOF) leads to reduced growth in Agrp1 morphant as well as Agrp1 mutant larvae. Further, it has been shown that multiple endocrine axes are dysregulated upon Agrp1 LOF in Agrp1 morphant larvae.

Risk Factors for Nonunion of Distal Femur Fractures.

Objectives: To determine patient, fracture, and construct related risk factors associated with nonunion of distal femur fractures.

Design: Retrospective cohort study.

Setting: Academic Level I trauma center.

The unique structural characteristics of the Kir 7.1 inward rectifier potassium channel: a novel player in energy homeostasis control.

The inward rectifier potassium channel Kir7.1, encoded by the gene, is a tetramer composed of two-transmembrane domain-spanning monomers, closer in homology to Kir channels associated with potassium transport such as Kir1.1, 1.

Hypo-osmolar rectal douche tenofovir formulation prevents simian/human immunodeficiency virus acquisition in macaques.

In spite of the rollout of oral pre-exposure prophylaxis (PrEP), the rate of new HIV infections remains a major health crisis. In the United States, new infections occur predominantly in men having sex with men (MSM) in rural settings where access to PrEP can be limited. As an alternative congruent with MSM sexual behavior, we have optimized and tested tenofovir (TFV) and analog-based iso-osmolar and hypo-osmolar (HOsm) rectal douches for efficacy against rectal simian/human immunodeficiency virus (SHIV) infection of macaques.

Risk of Acute Kidney Injury and Fracture-Related Infection After Antibiotic Prophylaxis With Piperacillin-Tazobactam in Open Fractures.

Objectives: To evaluate the effects of prophylactic piperacillin-tazobactam (PT) on inpatient acute kidney injury (AKI) and fracture-related infection (FRI) in patients with open fractures.

Setting: The study was conducted at a Level 1 trauma center.

Patients: We reviewed 358 Gustilo-Anderson type II and III open fractures at our institution from January 2013 to December 2017.

Improved Growth and High Inheritance of Melanocortin-4 Receptor (mc4r) Mutation in CRISPR/Cas-9 Gene-Edited Channel Catfish, Ictalurus punctatus.

Effects of CRISPR/Cas9 knockout of the melanocortin-4 receptor (mc4r) gene in channel catfish, Ictalurus punctatus, were investigated. Three sgRNAs targeting the channel catfish mc4r gene in conjunction with Cas9 protein were microinjected in embryos and mutation rate, inheritance, and growth were studied. Efficient mutagenesis was achieved as demonstrated by PCR, Surveyor® assay, and DNA sequencing.

Normalization of Elevated Blood Pressure After Anterior Cervical Discectomy and Fusion.

Perioperative change to the autonomic nervous system (ANS) in spine surgery is an uncommon occurrence but has a wide range of possible presentations including blood pressure, heart rate, and heart rate variability changes collectively referred to as dysreflexia. Increased sympathetic tone and decreased vagal output are believed to be the underlying causes of these autonomic manifestations and pose an important question as to effective treatment of these dysfunctions. Spinal nerve root decompression has shown to be a valuable tool in normalizing autonomic tone by increasing parasympathetic output, most notably to the cardiovascular system, leading to the resolution of the aforementioned cardiovascular complications.

Organization of neural systems expressing melanocortin-3 receptors in the mouse brain: Evidence for sexual dimorphism.

The central melanocortin system is fundamentally important for controlling food intake and energy homeostasis. Melanocortin-3 receptor (MC3R) is one of two major receptors of the melanocortin system found in the brain. In contrast to the well-characterized melanocortin-4 receptor (MC4R), little is known regarding the organization of MC3R-expressing neural circuits.

An Abnormal Presentation of Pediatric Genu Varum, Managed by Bilateral Tibial and Fibular Osteotomies With External Spatial Frame Placement: A Case Report.

Genu varum is a common finding in the pediatric population with a large differential, including but not limited to Blount's disease, rickets, and physiologic bowing of the legs. Here we report a case of a 12-year-old Caucasian male who presented for an atraumatic stress fracture of the fifth metatarsal after an athletic event. Further evaluation showed significant genu varum with a Q angle of 9 degrees and medial knee joint space narrowing.

An Abnormal Presentation of Multiple Myeloma in Pregnancy: A Case Report.

Multiple myeloma (MM) is an uncommon hematologic malignancy in the general population and extremely rare in pregnant and peripartum women. Here we report a rare case of multiple myeloma in a 43-year-old African American woman at 24 weeks gestation who presented for severe flank pain and difficulty breathing. An elevated D-dimer was present on initial presentation and diagnoses of deep vein thrombosis and pulmonary embolism were ruled out via bilateral Doppler ultrasounds and CT scan.